The present invention generally relates to a method for the diagnostic imaging of brain lesions, and more specifically to such a method in which labeled diagnostic agents are delivered across a chemically modified blood-brain barrier.
In diagnosing brain and central nervous system lesions, it is important to accurately characterize the type, size and extent of the lesions. This may be accomplished by the administration of chemical agents specific for lesion tissue which are labeled with appropriate diagnostic agents. However, materials used for this purpose are traditionally of high molecular weight and severely limited in their ability to penetrate the blood-brain barrier (BBB) of a patient. The BBB is a capillary barrier comprising a continuous layer of tightly bound endothelial cells. These cells permit a low degree of transendothelial transport, and exclude molecules in the blood from entering the brain on the basis of molecular weight and lipid solubility, as described in Neuwelt, E. A., "Is There a Therapeutic Role for Blood-Brain Barrier Disruption", Ann. Intern. Med. 93:137-139 (1980). For example, the BBB normally excludes molecules with a molecular weight greater than 180 daltons. In addition, the lipid solubility of molecules is a major controlling factor in BBB passage.
Considerable research has been conducted relating to the BBB and its permeability. Articles involving permeability of the BBB include:
1. "Chemotherapy of brain metastases: Current status", Greig, N. H., Cancer Treatment Reviews, 11:157-186 (1984). PA1 2. "Cerebrovascular permeability and delivery of gentamicin to normal brain and experimental brain abscess in rats", Neuwelt, E. A., et al, Journal of Neurosurgery, 61:430-439 (1984). PA1 3. "Blood-Brain Barrier: Phenomenon of Increasing Importance to the Imaging Clinician", Sage, M. R., American Journal of Roentgenology, 138:887-898 (1982). PA1 4. "Opening the Blood-Brain and Blood-Tumor Barriers in Experimental Rat Brain Tumors: The Effect and Intracarotid Hyperosmolar Mannitol on Capillary Permeability and Blood Flow", Hiesinger, E. M. et al, Annals of Neurology, 19:50-59 (1986).
The foregoing articles discuss the permeability characteristics of the BBB in terms of lipid solubility, ionization fraction, protein binding and/or the molecular weight of foreign molecules. As specifically described by Sage, the function of the BBB is to maintain the homeostasis of the neuronal environment. The continuity produced by the tight junctions between individual cells of the BBB enables the cerebrocapillary endothelium to act like a plasma membrane. Small molecules (m.w.&lt;200 daltons) having a high degree of lipid solubility and low ionization at physiological pH are freely passed through the BBB. In addition, the BBB allows water to move in either direction in order to maintain equal osmotic concentrations of solutes in the extracellular cerebral fluid.
However, recent research has shown that the BBB may become increasingly permeably during the development or onset of brain tumors, vascular lesions, or abscesses. As discussed by Sage, supra, the cerebrocapillary endothelium has a close investment by a glial sheath. Destruction of the glial sheath by mitotic activity may make the capillaries therein more permeable. Tumors appear to stimulate the proliferation of abnormal capillaries by releasing specific angiogenic factors in the brain.
The unique biological aspect of the BBB is an important focus in treating central nervous system disorders. While the interendothelial junctions between the cells of the BBB are normally designed to keep potentially noxious substances away from the brain, this condition changes during the formation of brain abscesses, inflammation, and/or tumors, as described above. For example, tests have shown that experimental allergic encephalomyelitis (EAE) may cause an immune reaction which increases the permeability of the BBB. Alvoode, E. C. et al, "Experimental Allergic Encephalomyelitis: A Useful Model For Multiple Sclerosis", Prog. Clin. Biol. Res., Vol. 146, Alan, R., Liss Co., N.Y. 1984. One explanation for the increased permeability of the BBB at the onset of EAE involves the capability of endothelial cells of the cerebrovasculature system to act as antigen present cells (APCs), thus attracting T-cells and aiding their penetration across the BBB. Accordingly, it has been found that brain endothelial cells are capable of expressing histocompatibility antigens on their surfaces.
Another possible explanation for the increase in permeability of the BBB during the onset of lesions involves the ability of the brain under these circumstances to generate vasoactive substances, as described in Black, K. L., "Leukotrienes Increase Blood-Brain Barrier Permeability Following Intraparenchymal Injections In Rats", Ann. Neurol., 18:349-351 (1985). Brain lips are rich in arachidonic acid which may be released by trauma to the brain tissue, e.g., by neoplastic invasion or ischemia. Black has shown experimentally that arachidonic acid and leukotrienes can increase BBB permeability when injected directly into the rat brain. Leukotriene content of the brain tissue correlates significantly with the amount of edema surrounding various CNS neoplasms, and it is conceivable that leukotrienes released from the damaged brain contribute to BBB disruption and vasogenic edema in CNS neoplasia.
Likewise, inflammation of brain tissue in immune-mediated CNS disease might possibly cause release of arachidonic acid and leukotrienes which would increase the permeability of the BBB. A further discussion of increased BBB permeability with reference to nervous system disorders, including infections, inflammatory conditions, neoplasms, and ischemia is presented in Fishman, R. A., Cerebrospinal Fluid in Diseases of the Nervous System, W. B. Saunders Co., Philadelphia, London, Toronto, 1980; Tourtelotte, W. "On Cerebrospinal IgG Quotients In Multiple Sclerosis and Other Diseases. A Review And A New Formula To Estimate The Amount of IgG Synthesized Per Day By the Central Nervous System", J. Neurol. Sci., 10:279-304 (1970).
With respect to the diagnosis of brain lesions, a variety of different techniques have been attempted. However, most of them encounter problems associated with the delivery of diagnostic imaging agents across the BBB. For example, one diagnostic procedure involves CT (computed tomography) scanning using a meglumine iothalamate imaging agent. Tests using this procedure have shown that meglumine iothalamate has difficulty passing through the BBB, and exhibits a high degree of neurotoxicity. In addition, this method is associated with an unacceptable degree of seizures in clinical trials as described in Neuwelt, E. A., et al, "Osmotic Blood Brain Barrier Modification: Clinical Documentation by Enhanced CT Scanning and/or Radionuclide Brain Scanning", Am. J. Neuroradiol., 4:907-913 (1983).
Another diagnostic method involves standard radionuclide imaging. This procedure is characterized by poor spatial resolution, and an inability to accurately image specific structures and regions in the brain. Also, time constraints exist when this method is used because of the short half-life of most radionuclides. For example .sup.99m TC is commonly used which has a half-life of about six hours.
Problems involving the accurate determination of brain lesion size are also present in other diagnosis methods including a recently perfected technique known as SPECT (single photon emission computerized tomography). Thus, a need currently exists for an improved method of diagnosing and characterizing brain lesions which avoids the problems described above, including impermeability of the BBB to diagnostic imaging agents. The present invention satisfies this need, as described herein.